WS01.4 VX-661 in combination with ivacaftor in patients with cystic fibrosis and the F508del-CFTR mutation

Abstract

Background The F508del and G551D mutations affect CFTR in different ways. VX-661 increases the quantity of functional F508del-CFTR at the cell surface, and ivacaftor (IVA) increases CFTR gating; effects are additive in vitro. Methods This randomized, double-blind, placebo-controlled, multi-cohort, phase 2 study evaluated escalating doses of VX-661 alone and in combination with IVA (150 mg q12h) in F508del/F508del patients, or the addition of VX-661 (100 mg qd) to F508del/G551D patients on prescribed IVA. Primary outcomes were safety and change in sweat chloride through Day 28. Percent predicted FEV 1 (ppFEV 1 ) was a secondary endpoint. Results The reported cohorts included 128 patients homozygous for F508del and 18 with F508del/G551D . In patients homozygous for F508del, at Day 28, VX-661 monotherapy resulted in reductions in sweat chloride but non-significant increases in ppFEV 1 , whereas VX-661/IVA decreased sweat chloride 5.7 mmol/L ( P 1 4.8 absolute points (P = 0.01 vs placebo; n=15). In F508del/G551D patients, through Day 28, VX-661/IVA led to a mean reduction in sweat chloride of 7.0 mmol/L ( P = 0.053; n=13) and significant within-group changes in absolute ppFEV 1 (4.6 points, P = 0.012; n=14). The overall incidence of AEs in VX-661/IVA-treated patients was similar across treatment groups and was comparable to placebo; the most common events were pulmonary exacerbation, cough, headache, nausea, and increased sputum. Conclusion These data show that the VX-661/IVA combination may benefit patients with CF who are homozygous for F508del and may enhance the benefit of IVA in CF patients with F508del/G551D.